Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or (c) a fall in the concentration of sodium in the distal tubules of the kidney.
When renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. The renin acts on a circulating protein, angiotensinogen, to cleave out a fragment called angiotensin I (AI). AI itself has only slight pharamacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII). The major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention. Sodium retention causes blood volume to increase, which leads to hypertension. AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to AII, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
Angiotensinogen, the natural substrate for human renin has the following amino acid sequence. ##STR2## Renin cleaves angiotensinogen at the amide bond between amino acid residues 10 and 11 to give angiotensin I (AI).
Compounds which are inhibitors of renin generally comprise two parts. One part of the compound mimics the first 9 amino acid residues of angiotensinogen. The other part mimics the Leu-Val cleavage site of angiotensinogen and is designed to be non-cleavable by renin. When these two parts are combined in one compound, the compound binds to renin but is not cleaved. Thus, renin is inhibited from acting on its natural substrate angiotensinogen.
Inhibitors of renin have been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
With these objectives in mind, the renin-angiotensin system has been modulated or manipulated, in the past, with ACE inhibitors. However, ACE acts on several substrates other than angiotensin I (AI), most notably the kinins which cause such undesirable side effects as pain, "leaky" capillaries, prostaglandin release and a variety of behavorial and neurologic effects. Further, ACE inhibition leads to the accumulation of AI. Although AI has much less vasoconstrictor activity than AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.
Inhibition of other targets in the renin-angiotensin system such as AII with compounds such as saralasin can block AII activity, but would leave unimpaired and perhaps enhance the hypertensive effects of AIII.
On the other hand, there are no known side effects which result when renin is inhibited from acting on its substrate. Considerable research efforts have thus been carried out to develop useful inhibitors of renin. Past research efforts have been directed to renin antibodies, pepstatin, phospholipids and substrate analogs such as tetrapeptides and octapeptides to tridecapeptides. These inhibitors either demonstrate poor activity in inhibiting renin production or poor specificity for inhibiting renin only. However, Boger et al. have reported that statine-containing peptides possess potent and specific renin-inhibiting activity (Nature, Vol. 303, p. 81, 1983). In addition, Szelke and co-workers have described polypeptide analogs containing a non-peptide link (Nature, Vol. 299, p. 555, 1982) which also cause potent renin inhibition and show a high specificity for this enzyme. Recent patents have disclosed novel small peptide renin inhibitors which contain novel dipeptide isosteres as transition state analogs (Szelke, et al., U.S. Pat. No. 4,609,643; Boger, et al., U.S. Pat. No. 4,668,770; Baran, et al., U.S. Pat. No. 4,657,931; Matsueda, et al., U.S. Pat. No. 4,548,926; Luly, et al., U.S. Pat. No. 4,645,759; and Luly, et al., U.S. Pat. No. 4,680,284).
The following references disclose peptide renin inhibitors which incorporate hydroxyl, substituted amide and heterocyclic derivatives of statine and statine analogs:
Luly, et al., U.S. Pat. No. 4,845,079, issued Jul. 4, 1989; PA0 Fung, et al., PCT Patent Application No. WO88/05050, published Jul. 14, 1988; PA0 Luly, et al., U.S. Pat. No. 4,725,584, issued Feb. 16, 1988; PA0 Luly, et al., U.S. Pat. No. 4,680,284, issued Jul. 14, 1987; PA0 Rosenberg, et al., U.S. Pat. No. 4,837,204, issued Jun. 6, 1989; PA0 Baran, et al., U.S. Pat. No. 4,657,931, issued Apr. 14, 1987; PA0 Matsueda, et al., U.S. Pat. No. 4,548,926, issued Oct. 22, 1985; PA0 Morisawa, et al., European Patent Application No. 0228192, published Jul. 8, 1987; PA0 Ten Brink, PCT Patent Application No. WO87/02986, published May 21, 1987; PA0 Buhlmayer, et al., U.S. Pat. No. 4,727,060, issued Feb. 23, 1988; PA0 Buhlmayer, et al., U.S. Pat. No. 4,758,584, issued Jul. 19, 1988; PA0 Szelke, et al., U.S. Pat. No. 4,713,445, issued Dec. 15, 1987; PA0 Raddatz, et al., U.S. Pat. No. 4,755,592, issued Jul. 5, 1988; PA0 Raddatz, et al., Australian Patent Application No. AU 76222/87, published Feb. 4, 1988; PA0 Ryono, et al., European Patent Application No. EP 0231919, published Aug. 12, 1987; PA0 Hanson, Biochem. Biophys. Res. Commun. 132 155 (1985); Luly, European Patent Application No. EP0189203, published Jul. 30, 1986; PA0 Hanson, et al., European Patent Application No. EP0310070, published Apr. 5, 1989; PA0 Hanson, et al., European Patent Application No. EP0310071, published Apr. 5, 1989; PA0 Hanson, et al., European Patent Application No. EP0310072, published Apr. 5, 1989; PA0 Hanson, et al., European Patent Application No. EP0310073, published Apr. 5, 1989; and PA0 Gante, et al., German Patent Application No. DE3721855, published Sep. 22, 1988. PA0 Boger, et al., U.S. Pat. No. 4,782,043, issued Nov. 1, 1988, discloses cyclic peptide renin inhibitors in combination with other antihypertensive agents. PA0 The term "substituted amino" as used herein refers to: PA0 I) alkylamino, PA0 II) dialkylamino, PA0 III) (hydroxyalkyl)(alkyl)amino, PA0 IV) (dihydroxyalkyl)(alkyl)amino, PA0 V) alkoxycarbonylalkylamino, PA0 VI) carboxyalkylamino, PA0 VII) (amino)carboxyalkylamino, PA0 VIII) ((N-protected)amino)carboxyalkylamino, PA0 IX) (alkylamino)carboxyalkylamino, PA0 X) ((N-protected)alkylamino)carboxyalkylamino, PA0 XI) (dialkylamino)carboxyalkylamino, PA0 XII) (amino)alkoxycarbonylalkylamino, PA0 XIII) ((N-protected)amino)alkoxycarbonylalkylamino, PA0 XIV) (alkylamino)alkoxycarbonylalkylamino, PA0 XV) ((N-protected)alkylamino)alkoxycarbonylalkylamino, PA0 XVI) (dialkylamino)alkoxycarbonylalkylamino, PA0 XVII) (alkoxyalkyl)(alkyl)amino, PA0 XVIII) (alkoxyalkoxyalkyl)(alkyl)amino, PA0 XIX) di-(alkoxyalkyl)amino, PA0 XX) di-(alkoxyalkoxyalkyl)amino, PA0 XXI) di-(hydrbxyalkyl)amino, PA0 XXII) ((unsubstituted heterocyclic)alkyl)(alkyl)amino, PA0 XXIII) ((substituted heterocyclic)alkyl)(alkyl)amino, ##STR135## wherein aa is 1 to 5 and R.sub.6 and R.sub.7 are independently selected from PA0 (I) --CHR.sub.13 R.sub.14 wherein PA0 (II) --C(.dbd.CH.sub.2)C(O)NHR.sub.15, PA0 (III) --C(OH)(R.sub.16)C(O)NHR.sub.15 or PA0 (IV) --CH(R.sub.16)C(O)NHR.sub.15 wherein PA0 (VI) --CH.sub.2 CH(R.sub.22)C(O)NHR.sub.23 wherein PA0 (IX) --CH.sub.2 CH(R.sub.81)NHC(O)R.sub.82 or --CH.sub.2 CH(R.sub.81)NHS(O).sub.2 R.sub.82 wherein PA0 (XI) --CF.sub.2 CH(OH)R.sub.83 wherein R.sub.83 is loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heterocyclic or (heterocyclic)alkyl. PA0 2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2-phenylethoxyhexan oic acid amide of 3-(1-imidazolyl)propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; PA0 2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2-phenylethoxyhexan oic acid amide of 3-(dimethylamino)propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; PA0 2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2-phenylethoxyhexan oic acid amide of 3-(4-morpholinyl)propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; PA0 N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl)-2-phenylethyl-L-noreucy l amide of 3-(1-imidazolyl)propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; and PA0 N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl)-2-phenylethyl-L-norleuc yl amide of 3-(4-morpholinyl)propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.
Boger, et al., U.S. Pat. No. 4,812,442, issued Mar. 14, 1989, discloses tripeptide renin inhibitors in combination with other antihypertensive agents.
Watkins, PCT Patent Application No. W087/02581, published May 7, 1987, discloses the use of renin inhibitors for the treatment of glaucoma.
Stein, et al., European Patent Application No. EP0311012, published Apr. 12, 1989, discloses renin inhibitors having a diol substituent which are anti-glaucoma agents.
Peptidyl inhibitors of HIV protease are disclosed by Moore, Biochem. Biophys. Res. Commun., 159 420 (1989); Billich, J. Biol. Chem., 263 1790S (1988); and Richards, FEBS Lett., 247 113 (1989).